Potential of therapeutic plasmapheresis in treatment of COVID-19 patients: Immunopathogenesis and coagulopathy.

Therapeutic plasmapheresis (TP) is the process of the separation and removal of plasma from other blood components and is considered as an adjunctive treatment strategy to the discarded abnormal agent in the management of respiratory viral pandemics. This article reviews the mechanisms of immunopathogenesis and coagulopathy induced by SARS-CoV-2 and the potential benefits of TP as adjunctive treatment in critically COVID-19 patients.

Cost-effectiveness of point-of-care viscoelastic haemostatic assays in the management of bleeding during cardiac surgery: protocol for a prospective multicentre pragmatic study with stepped-wedge cluster randomised controlled design and 1-year follow-up (the IMOTEC study).

INTRODUCTION: During cardiac surgery-associated bleeding, the early detection of coagulopathy is crucial. However, owing to time constraints or lack of suitable laboratory tests, transfusion of haemostatic products is often inappropriately triggered, either too late (exposing to prolonged bleeding and thus to avoidable administration of blood products) or blindly to the coagulation status (exposing to unnecessary haemostatic products administration in patients with no coagulopathy). Undue exposition to transfusion risks and additional healthcare costs may arise. With the perspective of secondary care-related costs, the IMOTEC study (Intérêt MédicO-économique de la Thrombo-Elastographie, dans le management transfusionnel des hémorragies péri-opératoires de chirurgies Cardiaques sous circulation extracorporelle) aims at assessing the cost-effectiveness of a point-of-care viscoelastic haemostatic assay (VHA: RoTem or TEG)-guided management of bleeding. Among several outcome measures, particular emphasis will be put on quality of life with a 1-year follow-up. METHODS AND ANALYSIS: This is a multicentre, prospective, pragmatic study with stepped-wedge cluster randomised controlled design. Over a 36-month period (24 months of enrolment and 12 months of follow-up), 1000 adult patients undergoing cardiac surgery with cardiopulmonary bypass will be included if a periprocedural significant bleeding occurs. The primary outcome is the cost-effectiveness of a VHA-guided algorithm over a 1-year follow-up, including patients' quality of life. Secondary outcomes are the cost-effectiveness of the VHA-guided algorithm with regard to the rate of surgical reexploration and 1-year mortality, its cost per-patient, its effectiveness with regard to haemorrhagic, infectious, renal, neurological, cardiac, circulatory, thrombotic, embolic complications, transfusion requirements, mechanical ventilation free-days, duration of intensive care unit and in-hospital stay and mortality. ETHICS AND DISSEMINATION: The study was registered at Clinicaltrials.gov and was approved by the Committee for the Protection of Persons of Nantes University Hospital, The French Advisory Board on Medical Research Data Processing and the French Personal Data Protection Authority. A publication of the results in a peer-reviewed journal is planned. TRIAL REGISTRATION NUMBER: NCT02972684; Pre-results.

Real-Time Ultrasound-Guided Paracentesis by Radiologists: Near Zero Risk of Hemorrhage without Correction of Coagulopathy.

PURPOSE: To evaluate the rate and risk factors for hemorrhage in patients undergoing real-time, ultrasound-guided paracentesis by radiologists without correction of coagulopathy. MATERIALS AND METHODS: This was a retrospective study of all patients who underwent real-time, ultrasound-guided paracentesis at a single institution over a 2-year period. In total, 3116 paracentesis procedures were performed: 757 (24%) inpatients and 2,359 (76%) outpatients. Ninety-five percent of patients had a diagnosis of cirrhosis. Mean patient age was 56.6 years. Mean international normalized ratio (INR) was 1.6; INR was > 2 in 437 (14%) of cases. Mean platelet count was 122 x 103/µL; platelet count was < 50 x 103/µL in 368 (12%) of patients. Seven hundred seven (23%) patients were dialysis dependent. Patients were followed for 2 weeks after paracentesis to assess for hemorrhage requiring transfusion or rescue angiogram/embolization. Univariate analysis was performed to determine risk factors for hemorrhage. Blood product and cost saving analysis were performed. RESULTS: Significant post-paracentesis hemorrhage occurred in 6 (0.19%) patients, and only 1 patient required an angiogram with embolization. No predictors of post-procedure bleeding were found, including INR and platelet count. Transfusion of 1125 units of fresh frozen plasma and 366 units of platelets were avoided, for a transfusion-associated cost savings of $816,000. CONCLUSIONS: Without correction of coagulation abnormalities with prophylactic blood product transfusion, post-procedural hemorrhage is very rare when paracentesis is performed with real-time ultrasound guidance by radiologists.

Activity-based costs of plasma transfusions in medical and surgical inpatients at a US hospital.

BACKGROUND AND OBJECTIVES: Fresh frozen plasma (FFP) usage has significantly increased over the last decade leading to elevated healthcare costs. Although FFP is used in several clinical settings, it is often inappropriately transfused and evidence for its clinical efficacy is poor. Here, we describe plasma usage and transfusion costs in a real-world US inpatient setting to determine the cost-effectiveness of FFP transfusion and for comparison to various patient blood management (PBM) options to treat coagulopathies. MATERIALS AND METHODS: All activities related to plasma transfusion recorded at a single US hospital over one calendar year were collected in a stepwise manner using an activity-based costing (ABC) methodology. This model maps all technical, administrative and clinical processes inherent to the cost of plasma. RESULTS: Of 18 200 inpatients recorded, 849 were charged for blood products. In total, 136 medical and surgical inpatients were charged for 577 units of FFP, receiving a total of 534 units; 43 units were charged but not transfused. The total cost per unit of FFP transfused was $409·62 and $1,608·37 per patient transfused with FFP. Wasted products, in-hospital processes and overhead costs were found to account for 89·8% of the total cost of FFP transfusions. CONCLUSION: This study is the first to use ABC methodology to determine the full cost of plasma transfusion in a US inpatient setting. These data reveal the true cost of plasma, providing a useful reference point to compare with the cost of other PBM options to manage coagulation disorders.

Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs.

INTRODUCTION: Hemorrhage is the principal cause of death in the first few hours following severe injury. Coagulopathy is a frequent complication of critical bleeding. A network of Italian trauma centers recently developed a protocol to prevent and treat trauma-induced coagulopathy. A pre-post cohort multicenter study was conducted to assess the impact of the early coagulation support (ECS) protocol on blood products consumption, mortality and treatment costs. METHODS: We prospectively collected data from all severely injured patients (Injury Severity Score (ISS) >15) admitted to two trauma centers in 2013 and compared these findings with the data for 2011. Patients transfused with at least 3 units of packed red blood cells (PRBCs) within 24 hours of an accident were included in the study. In 2011, patients with significant hemorrhaging were treated with early administration of plasma with the aim of achieving a high (≥1:2) plasma-to-PRBC ratio. In 2013, the ECS protocol was the treatment strategy. Outcome data, blood product consumption and treatment costs were compared between the two periods. RESULTS: The two groups were well matched for demographics, injury severity (ISS: 32.9 in 2011 versus 33.6 in 2013) and clinical and laboratory data on admission. In 2013, a 40% overall reduction in PRBCs was observed, together with a 65% reduction in plasma and a 52% reduction in platelets. Patients in the ECS group received fewer blood products: 6.51 units of PRBCs versus 8.14 units. Plasma transfusions decreased from 8.98 units to 4.21 units (P <0.05), and platelets fell from 4.14 units to 2.53 units (P <0.05). Mortality in 2013 was 13.5% versus 20% in 2011 (13 versus 26 hospital deaths, respectively) (nonsignificant). When costs for blood components, factors and point-of-care tests were compared, a €76,340 saving in 2013 versus 2011 (23%) was recorded. CONCLUSIONS: The introduction of the ECS protocol in two Italian trauma centers was associated with a marked reduction in blood product consumption, reaching statistical significance for plasma and platelets, and with a non-significant trend toward a reduction in early and 28-day mortality. The overall costs for transfusion and coagulation support (including point-of-care tests) decreased by 23% between 2011 and 2013.

Routine preoperative blood testing in pediatric neurosurgery.

OBJECT: The frequency with which routine preoperative blood test results predict perioperative or postoperative complications is insignificant. The unnecessary ordering of routine tests increases the financial costs and patients' distress. The authors evaluated the effects of routine preoperative testing on patient management and the overall financial costs. METHODS: The authors retrospectively reviewed the medical records and laboratory data for 355 children admitted to the neurosurgical department for elective procedures over a 5-year period (January 2008-December 2012). They excluded all patients admitted for imaging or surgical procedures requiring local anesthesia, and they recorded the results of preoperative and previous (up to 6 months before surgery) blood tests and any abnormalities noted. RESULTS: As a result of the 3489 blood tests ordered preoperatively for 328 (94.6%) of the 355 patients, 29 abnormalities (9%) were detected. Most of these abnormal values were near the reference range, and none significantly affected the progression of scheduled procedures. For only 1 patient (0.28%) was the procedure cancelled because of an abnormality (preoperative partial thromboplastin time), which further testing showed to be a false-positive result. The cost of these tests over 5 years was 5205-10,410 euros ($6766-$13,533 US). CONCLUSIONS: Preoperative tests should be selectively requested on the basis of clinical indication.

[Documentation of haemophilia treatment supported by the German Hemophilia Registry]. / Dokumentation in der Hämophilietherapie mit Unterstützung des Deutschen Hämophilieregisters.

The DHR (Deutsches Hämophilieregister, German Haemophilia Register) records patient data on haemophilia A, haemophilia B, von Willebrand disease, and other coagulation factor deficiency disorders. The DHR has been online since 2009. The participation in the DHR leads to additional administrative workload for the hospitals and physicians, but provides many advantages as well: A standard of documentation will be developed to give evidence for the hospitals. They may use their own data as well as with new possibilities for data processing at any time. Reports in accordance with Section21 TFG (Transfusionsgesetz, German Transfusion Act) are compiled automatically and transmitted to the Paul-Ehrlich-Institut. The DHR may support the searching for patients fulfilling the requirements for participation in a study.

Postoperative acquired coagulopathy: a pilot study to determine the impact on clinical and economic outcomes.

STUDY OBJECTIVE: To characterize the clinical factors associated with postoperative acquired coagulopathy, and to estimate the economic impact of resources used to treat postoperative patients with this coagulopathy compared with postoperative patients who did not develop the coagulopathy. DESIGN: Case-control study. SETTING: Academically affiliated public hospital and level I trauma referral center. PATIENTS: Twenty-six patients (mean age 53.9 yrs) who experienced acquired coagulopathy after undergoing an index surgery (cases), and 26 patients (mean age 50.8 yrs) matched to these case patients by index surgery, age, and sex (controls). MEASUREMENTS AND MAIN RESULTS: Data were collected from a database of 5367 adult surgical admissions over 6 months during 2008, corresponding inpatient electronic health records, billing data, and Medicare Resource-Based Relative Value Scale payments. Case patients had a minimum of two postoperative consecutively drawn episodes of prothrombin time (PT) or activated partial thromboplastin time (aPTT) elevated to greater than 20% above the upper limit of normal. Patients with inherited clotting disorders or other identifiable causes of coagulopathy were excluded. Case patients underwent the following surgeries: 12 orthopedic (46%), six cardiovascular (23%), four gastrointestinal (15%), and four neurosurgical (15%). Mean values of the first elevated PT and aPTT were 19.7 and 50.8 seconds, respectively. Mean postoperative stay was 31.5 days for cases versus 9.8 days for controls (p<0.05). Mean cost (2008 U.S. dollars) of resources used was $112,280 for cases versus $38,357 for controls (p<0.001). Costs incurred between the onset of coagulopathy and discharge constituted 67% of postoperative costs. Physician reimbursement expenditures were minimal. CONCLUSION: Postoperative acquired coagulopathy was associated with stays that were 3 times longer and resource use costs that were 3 times higher than those of controls. This type of coagulopathy may be an under-recognized and underappreciated event. The case-control design is limited to exploring associations and does not establish causality. Prospective studies need to be conducted to establish the causes of acquired coagulopathy and methods for screening and diagnosing this condition.

[Perioperative coagulation monitoring - medical and economic aspects]. / Perioperative Gerinnungsdiagnostik - Medizinische und ökonomische Perspektiven.

For preoperative haemostatic assessment a structured questionnaire for the bleeding history of the patient should be primarily used. Only in case of abnormalities an additional laboratory coagulation testing is recommended. Such a test set must include functional testing of platelets as defects of the primary haemostasis are frequent. In the event of acute acquired perioperative coagulopathy laboratory coagulation testing is a prerequisite for sophisticated and precise diagnosis and therapy. Points of care techniques like thrombelastography are capable to provide fast and extensive information.

Thrombin products: economic impact of immune-mediated coagulopathies and practical formulary considerations.

Thrombin has demonstrated utility in aiding surgical hemostasis since its introduction more than 60 years ago. It is used across a wide variety of surgical procedures by virtually every specialty. Only recently have new equally effective and safe products entered the market, causing decision makers to evaluate formulary selection among products with otherwise modest differences. This evaluation includes identifying costs beyond those of acquisition and storage, as well as indirect factors such as monitoring or specialized distribution requirements. One factor to consider specifically in selection of topical thrombin products is the potential for patients to develop an immune-mediated coagulopathy (IMC) after exposure to bovine-derived thrombin. Costs due to adverse drug events fall into the category of indirect costs and, in some instances, can be substantial if bleeding due to IMC occurs.

Cost reduction of perioperative coagulation management in cardiac surgery: value of "bedside" thrombelastography (ROTEM).

OBJECTIVE: Demographic changes and aggressive platelet inhibition have resulted in a marked increase in blood- and coagulation product expenditure and costs in cardiac surgery. We analyzed "bedside" coagulation test (ROTEM) in order to verify clot forming quality for the purpose of finding a cost-effective treatment path. METHODS: Annual treatment costs of all cardiosurgical patients were analyzed before (729 patients) and after (693 patients) implementation of "bedside" ROTEM. Cumulative numbers and costs of platelet concentrates (PltC), fresh frozen plasma (FFP), red blood cell units (RBC), and coagulation factors: pooled coagulation concentrates (PCC), recombinant factor VIIa (rFVIIa), factor XIII (FXIII), and fibrinogen were assessed. Average monthly numbers and costs were compared. Number of resternotomies and early mortality was assessed and compared in both periods. RESULTS: After ROTEM implementation cumulative RBC expenditure showed 25% decrease while PltC exhibited 50% decrease. FFP expenditure remained unchanged. PCC, FXIII were markedly reduced (-80%) while rFVIIa were entirely omitted. Fibrinogen, however, increased two-fold. Cumulative average monthly costs of all blood products decreased from 66,000 euro to 45,000 euro (-32%). Coagulation factor average monthly costs decreased from 60,000 euro to 30,000 euro (-50%) yielding combined savings of 44%. In contrast, average monthly costs for ROTEM were 1.580 euro. Total number of resternotomies decreased from 6.6% to 5.5% while early mortality (5.9%; 6.0%) remained stable. CONCLUSION: Cumulative costs for treatment of perioperative coagulation disorders can be reduced by "bedside" ROTEM analysis to achieve a selective substitution management. Saved costs for blood- and coagulation products clearly outweighed the expenses of ROTEM. Adequate differential coagulation management can therefore be cost-effective.

Perinatal stroke in baby, prothrombotic gene in mom: does this affect maternal health insurance?

BACKGROUND: Maternal prothrombotic disorders may contribute to stroke in the fetus before and during birth. Many of the mothers of children with perinatal stroke have no previous history of pathologic thrombosis. OBJECTIVE: To determine if finding the Factor V Leiden mutation, prothrombin 20210 G-A gene defect, or methylene tetrahydrofolate reductase C677T mutation in an asymptomatic mother of a child with perinatal stroke would affect that mother's ability to obtain health insurance. METHODS: 1) The authors reviewed the literature on genetic prothrombotic risk factors and health insurance. 2) The authors surveyed the 17 largest insurance carriers in Indiana to find if diagnosing genetic prothrombotic risk factors in asymptomatic mothers of children with perinatal stroke would affect the mothers' health insurance status. RESULTS: Three articles on genetic prothrombotic risk factors and insurance were identified. Twelve of 17 insurance companies responded to our survey; three had policies on genetic testing. Most companies refused to provide clear, useful information on their policies regarding these risk factors. CONCLUSIONS: The authors are currently unable to counsel their patients' families on the long-term insurance implications of screening for genetic prothrombotic risk factors. The insurance implications of diagnosing healthy women with genetic prothrombotic risk factors need further study.

Successful reversal of deleterious coagulopathy by recombinant factor VIIa.

Effective treatment of severe or uncontrolled bleeding is a challenge for physicians in the operating room and intensive care unit. However, even aggressive conventional therapy may ultimately fail in some patients. Administration of recombinant activated factor VII (rFVIIa) may be the only remaining therapeutic option to stop life-threatening coagulopathic bleeding. We here describe the clinical course of 5 patients exhibiting severe continuous bleeding that could not be stopped by surgical intervention and appropriate hemostatic management but resolved after a mean dose of 90 microg/kg of rFVIIa (range, 90-120 microg/kg). Four of the five patients recovered completely, and one patient died after developing sepsis in multiorgan failure. In all patients, bleeding from wound surfaces stopped within minutes of the administration of rFVIIa. Coagulation measurements improved, and transfusion requirements declined considerably. No adverse effects associated with rFVIIa were observed.

[Can we afford the costs of progress in intensive care medicine? A plea for a candid debate]. / Können wir uns die Fortschritte der Intensivmedizin noch leisten? Ein Plädoyer für eine offenen Debatte.

Intensive care medicine is one of the most fast growing segments in medicine. New substances that may improve therapy of the critically ill dramatically have entered the market. Improvements include therapy of methicilline-resistant Staphylococcus aureus (MRSA) infections (linezolid), severe heart failure (calcium sensitizer levosimendan), intractable bleeding (recombinant factor VIIa) and severe sepsis (recombinant activated protein C (aPC)). The anticipations concerning this new strategies of intensive care therapy are high, but use of the new substances is associated with extreme costs. In the past, pharmaceutical therapy represented only a small aspect of all costs in the intensive care unit (ICU). Using this new substances, we are entering a new dimension of costs. One case of recombinant factor VIIa or recombinant aPC increases costs by approximately 10000,- Euro. At the moment, this costs are not covered by extra-budgets. It is still unclear whether by using this new therapeutic strategies other costs can be reduced and the extreme extra-costs can be balanced. The elderly population will increase dramatically in the next years. Looking at this development, it is not only the question whether we can afford intensive care medicine, but the question has to be enlarged whether we can afford the new developments of intensive care medicine. All responsible persons (intensivists, pharmaceutical companies, politicians) are urged to define solutions in the near future.